The present invention relates to treating ocular disorders and more particularly to treating glaucoma. U.S. Pat. Nos. 5,798,380, 6,110,912, and 6,586,425, each of which is incorporated herein by reference as if set forth in its entirety, describe in detail the nature and etiology of glaucoma and various therapeutic approaches for reducing intraocular pressure characteristic of the disorder. The incorporated patents disclose methods for enhancing aqueous humor outflow and reducing intraocular pressure in the eye of a subject by administering at least one non-corneotoxic ophthalmic preparation which can comprise at least one macrolide. Additional therapeutic modalities employing other agents are still sought.
Caldesmon, a protein found in smooth muscle and non-muscle cells, causes secondary degeneration of the actin-microfilament network and thereby interferes with actomyosin contractility and with formation of focal cell adhesions. Helfman, D. M., et al., “Caldesmon inhibits non-muscle cell contractility and interferes with the formation of focal adhesions,” MBC 10:3097 (1999), incorporated herein by reference as if set forth in its entirety. Caldesmon, which contains actin-, myosin-, tropomyosin-, and Ca2+-calmodulin-binding domains, inhibits an ATPase activity of actomyosin, blocks the interaction of actin with myosin, prevents myosin II-dependent cell contractility, and induces a decrease in number and size of tyrosine-phosphorylated focal adhesions. In the absence of calcium-calmodulin, caldesmon binds filamentous actin (“F-actin”). While various activities of caldesmon are known in general, there is no prior indication of advantageous drainage-enhancing and pressure-reducing activities by caldesmon in animal eyes.
A nucleic acid sequence that encodes caldesmon in humans is known and is disclosed at GenBank at Accession Number NM—033138 (variant 1), provided herein at SEQ ID NO:1 with the encoded caldesmon protein (from nucleotides 460–2838) being provided at SEQ ID NO:2. Several known transcription variants employ the same underlying nucleic acid sequence and are accessible at Accession Numbers NM—004342 (variant 2; coding portion from nucleotides 460–2076), NM—033157 (variant 3; coding portion from nucleotides 460–2154), NM—033139 (variant 4; coding portion from nucleotides 214–1890) and NM—033140 (variant 5; coding portion from nucleotides 214–1812). Variants 2–5 are expressed principally in non-muscle tissues, while variant 1 is expressed principally in muscle. The UniGene accession number for human caldesmon is Hs.490203. Other caldesmon-encoding sequences are known. For example, a nucleic acid sequence that encodes caldesmon in rat is known and is disclosed at GenBank at Accession Number NM—013146 (version 2). The sequence of NM—013146 (version 2) is provided herein at SEQ ID NO:3 with the encoded rat caldesmon protein (coding portion from nucleotides 156–1751) being provided at SEQ ID NO:4.